tbuckley/cabot-search huggingface dataset:
Abstract LB029: AWT030: a first-in-class bi-functional IL-21 fusion protein selectively activates tumor infiltrated CD8 T cells and suppresses Treg cells
Authors: Fan Ye, Jianing Huang, Sandra Chen, Ella Li, Jenny Jiang, Hanna Lin, Michael Hua, Danny Huang, Zoey Huang, Joyce Kwan, Lili Cheng, Ziyang Zhong
Journal: Cancer Research (2023)

Abstract The tumor microenvironment (TME) has been identified as a significant obstacle to the success of immunotherapy, including anti-PD-1 therapy. The TME comprises several factors that limit the response rate to immunotherapy, including immunosuppressive cells such as regulatory T cells (Tregs), which directly or indirectly interact with effector cells and undermine the tumor recognition, activation, proliferation, and survival of the effector cells, thereby promoting tumor growth. To overcome suppressive TME, we designed AWT030, a first-in-class bi-functional IL-21 fusion protein that comprises a stability and potency optimized IL-21 mutein and an engineered functional domain that targets T cells. AWT030 is designed to selectively activate tumor-infiltrating CD8 T cells and suppress Tregs while avoiding the potential suppressive effect of IL-21 on dendritic cells.Compared to wild-type IL-21, mAWT030 greatly enhances the tolerability, half-life, and anti-tumor activity. In anti-PD-1 therapy resistant breast cancer EMT6 model, fibrosarcoma MCA205 model, and anti-PD-1 therapy responsive colon cancer MC38 model, mAWT030 achieved 100% complete response without noticeable toxicity, demonstrating a powerful synergy between tumor specific CD8 T cell activation axis and Treg suppression axis induced simultaneously by mAWT030. In addition, mAWT030 also exhibited a strong synergistic effect with anti-PD-1 antibody. Immunophenotyping revealed that AWT030 had minimal impact on circulating lymphocytes while altering the suppressive TME, with a significantly increased CD8 T cell population and suppressed Treg population. In summary, AWT030 is a novel bi-functional IL-21 fusion protein with high tumoral specificity, the excellent safety and antitumor activity of mAWT030 observed preclinically supports clinical development, focusing on treating PD-1 resistant/relapsed patients or combining with anti-PD-1 therapy. Citation Format: Fan Ye, Jianing Huang, Sandra Chen, Ella Li, Jenny Jiang, Hanna Lin, Michael Hua, Danny Huang, Zoey Huang, Joyce Kwan, Lili Cheng, Ziyang Zhong. AWT030: a first-in-class bi-functional IL-21 fusion protein selectively activates tumor infiltrated CD8 T cells and suppresses Treg cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB029.
Abstract CT240: On-going phase 1A clinical trial for AG01 an first-in-class anti-progranulin (GP88) monoclonal antibody in patients with advanced malignancies
Authors: Katherine R. Tkaczuk, Paula Rosenblatt, Ranee Mehra, Katherine A. Scilla, Nancy Tait, Katerra Caple, Binbin Yue, Ginette Serrero
Journal: Cancer Research (2023)

Abstract Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats which is the largest member of the granulin-epithelin protein family. PGRN/GP88 has been demonstrated as a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC), lung prostate, ovarian and digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence in breast, lung cancers while elevated serum PGRN/GP88 level in metastatic breast, lung, ovarian and prostate cancer patients. Elevated PGRN/GP88 levels are associated with poor outcomes such as progression and shortened survival. An anti-human PGRN/GP88 monoclonal antibody able to inhibit PGRN/GP88 action in vitro and in vivo has been developed, chimerized and expressed in CHO cells. All IND enabling activities including pharmacology, GMP manufacturing, formulation and GLP toxicology studies have been conducted. The IND application has been filed and cleared by the Food and Drug Administration. A first-in-human, first-in-class phase 1 safety and efficacy clinical study of AG01 in patients with solid tumors and advanced disease with special focus on patients with breast, lung and ovarian cancers has been initiated and is on-going at the University of Maryland Greenebaum Cancer Center. The trial is registered as NCT05627960 to clinicaltrials.gov site. Supported by grants R44CA162629 and R44CA224718 from the National Cancer Institute to GS. Citation Format: Katherine R. Tkaczuk, Paula Rosenblatt, Ranee Mehra, Katherine A. Scilla, Nancy Tait, Katerra Caple, Binbin Yue, Ginette Serrero. On-going phase 1A clinical trial for AG01 an first-in-class anti-progranulin (GP88) monoclonal antibody in patients with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT240.
Abstract LB004: Ultra-sensitive targeted DNA panel for very low-frequency mutation detection in circulating cell-free DNA
Authors: Michelle Baird, Mariam Ashraf, Emil Chistensen, Christa Haldrup, Zhong Wu, Eric Lader
Journal: Cancer Research (2023)

Abstract Due to its noninvasive nature and being readily available in peripheral blood and other bodily fluids, analysis of cell-free DNA (cfDNA) has become a promising application in cancer diagnosis, prognosis and treatment monitoring. However, disease-relevant cfDNA is present in a very limited amount in the huge background of normal cfDNA. This remains a challenge for any detection technology. Many currently available target enrichment and library preparation methods use regular DNA polymerase and amplification processes that introduce substantial bias and artifacts. This results in artifactual errors that greatly limit the detection of true low-frequency variants below 0.5% in heterogeneous samples, such as cfDNA. Here, we present a new targeted cfDNA workflow that overcomes challenges such as biases and artifacts. The workflow uses a highly optimized, high-fidelity reaction chemistry and incorporates UMIs into a single gene-specific, primer-based targeted enrichment process. Compared to regular DNA polymerase, this high-fidelity chemistry resulted in a five- to ten-fold decrease in base substitution error. An individual cancer panel was designed to specifically cover cancer-relevant hotspots and copy number genes with a dense primer design to accommodate the short length of cfDNA. Due to its high-fidelity chemistry and optimal panel design, our streamlined workflow can be completed in a single day. We also report consistent panel performance across different samples. Detection sensitivity and specificity were evaluated on a reference cfDNA sample and a simulated cfDNA sample by mixing enzyme-digested Genome in a Bottle samples, NA12878 and NA24385. We achieved close to 90% detection sensitivity and above 99.9% specificity for 0.1% variant. In addition, copy number variation could be successfully detected with a 1.5-fold difference over normal control samples. These results demonstrate an efficient targeted cfDNA panel workflow that enables cancer-relevant mutation detection with high sensitivity and accuracy. The applications presented here are for research use only. Not for use in diagnostic procedures. Citation Format: Michelle Baird, Mariam Ashraf, Emil Chistensen, Christa Haldrup, Zhong Wu, Eric Lader. Ultra-sensitive targeted DNA panel for very low-frequency mutation detection in circulating cell-free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB004.
Abstract CT137: ENLIGHTen-01: a phase 1 study of fluorescein-specific (FITC-E2)-car T cells in combination with folate-fluorescein (UB-TT170) for osteosarcoma
Authors: Catherine M. Albert, Navin R. Pinto, Mallory Taylor, Ashley Wilson, Stephanie Rawlings-Rhea, Prabha Narayanaswamy, Wenjun Huang, Kristy Seidel, Stephanie Mgebroff, Christopher Brown, Jacob Garcia, Jeffrey Teoh, Rimas J. Orentas, Rebecca A. Gardner, Michael C. Jensen, Julie R. Park
Journal: Cancer Research (2023)

Abstract Background: Outcomes for relapsed osteosarcoma (OS) remain poor and there are no systemic therapies that have been shown to provide a survival benefit. Chimeric Antigen Receptor (CAR) T cell immunotherapy involves the adoptive transfer of T-lymphocytes that have been engineered to recognize tumor-specific antigens, resulting in targeted lysis of malignant cells. Folate receptors (FR) are membrane-bound surface proteins that bind folates with high affinity. FRs are overexpressed in OS and have very limited expression in normal tissue. UB-TT170 (Umoja Biopharma) is a small molecule bispecific “adapter” consisting of folate conjugated to fluorescein (FL). It penetrates tumors in minutes and is retained for long periods of time due to high affinity for the FR, while unbound UB-TT170 rapidly clears from the blood and from FR- tissues. We hypothesize that administration of fixed dosing anti-FL(FITC-E2) CAR T cells followed by escalating doses of UB-TT170 will deliver personalized immunotherapy to OS patients. In addition, this approach offers an attractive safety mechanism since administration of NaFL should reverse CAR T cell reactivity. Methods: We designed a Phase I study for young adult (15-30 yr) patients with recurrent/refractory OS to examine the safety and feasibility of administering autologous, peripheral blood-derived T cells that have been genetically modified to express a 2nd generation FL-specific CAR in combination with intra-subject dose escalation of UB-TT170. The primary objective is to identify a recommended dose escalation sequence of UB-TT170 to move forward in clinical development. A 3+3 design will be used to investigate 3 possible dosing sequences. The trial opened in July 2022. As of January 5, 2023, 5 subjects have enrolled and one subject has been treated on dose regimen 1. T cell products have been successfully manufactured for all enrolled subjects. The trial remains open to enrollment. Clinical trial registration numbers: NCT05312411 Citation Format: Catherine M. Albert, Navin R. Pinto, Mallory Taylor, Ashley Wilson, Stephanie Rawlings-Rhea, Prabha Narayanaswamy, Wenjun Huang, Kristy Seidel, Stephanie Mgebroff, Christopher Brown, Jacob Garcia, Jeffrey Teoh, Rimas J. Orentas, Rebecca A. Gardner, Michael C. Jensen, Julie R. Park. ENLIGHTen-01: a phase 1 study of fluorescein-specific (FITC-E2)-car T cells in combination with folate-fluorescein (UB-TT170) for osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT137.
Abstract LB272: Spatial cellular architecture predicts prognosis in glioblastoma
Authors: Yuanning Zheng, Francisco Carrillo-Perez, Marija Pizurica, Olivier Gevaert
Journal: Cancer Research (2023)

Abstract Intra-tumoral heterogeneity and cell-state plasticity are key drivers for the therapeutic resistance of glioblastoma (GBM). Studies based on single-cell RNA-seq and spatial transcriptomics have classified GBM cells into distinct transcriptional phenotypes. However, how the transcriptional diversity and spatial cellular organization are associated with patient prognosis remains incompletely resolved. Here, we developed a deep learning model to predict spatially resolved transcriptional programs from histology images. The model was trained on spatial transcriptomics data and validated in external testing cohorts. Applying the model to two separate patient cohorts led to the discovery of conserved relationships between tumor architecture and prognosis. Patient with poor prognosis had higher proportions of GBM cells expressing a hypoxia-induced transcriptional program. In addition, high clustering patterns of reactive astrocytes were associated with a poor prognosis. Conversely, when the reactive astrocytes were dispersed and connected to other cell types, the risk was decreased. To validate our results, we developed a separate deep learning model that used histology images to predict prognosis. Applying the model to spatial transcriptomics data discovered survival-associated regional gene expression programs. Genes related to glycoprotein metabolism and injury response were significantly upregulated in tumor cells with high aggressiveness. Our studies established a scalable approach to resolve the transcriptional heterogeneity of GBM and linked the spatial cellular architecture to clinical outcomes. Citation Format: Yuanning Zheng, Francisco Carrillo-Perez, Marija Pizurica, Olivier Gevaert. Spatial cellular architecture predicts prognosis in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB272.
Abstract LB357: CRISPR-Cas9 targeting of somatic mutations selectively kills cancer cells
Authors: Kirsten Bowland, Selina Shiqing K. Teh, Alyza Skaist, Ralph H. Hruban, Nicholas J. Roberts, Chrisine Iacobuzio-Donahue, James R. Eshleman
Journal: Cancer Research (2023)

Abstract Pancreatic ductal adenocarcinoma (PDAC) accounts for 3% of all cancers but is the 3rd leading cause of cancer death in the United States. This staggering discrepancy is partly because most pancreatic cancers evade early detection and patients most commonly present with metastatic disease. As cancer initiates from a single transformed cell, passenger mutations that accumulate over the course of the patient’s lifetime in that cell are then clonally propagated to the growing tumor and metastases, providing a targetable molecular signature throughout the cancer. Here we propose a CRISPR-Cas9 gene therapy aimed at these tumor-specific somatic mutations. Using whole genome sequencing of rapid autopsy tumor and normal samples from five patient cases, we identified single base substitutions present in tumor tissues and absent in patient-matched normal tissue. A subset (6.6% on average) of these mutations lead to novel protospacer adjacent motif (PAM) sites. These tumor specific PAM sites are necessary for Cas9 binding and DNA scission and are therefore selectively targetable by CRISPR-Cas9 systems. Using a hybrid capture/NGS approach, we demonstrate in patients with multiple metastases that the majority of these novel PAM sites, ~70%, are maintained among the different metastases. Using multitarget sgRNA which cut at a known number of sites in the human genome, we determined a relationship between number of CRISPR-Cas9 cuts and growth inhibition in PDAC cells. We found that 8-10 cut sites in non-coding regions are sufficient to induce &amp;gt;95% cancer cell death. Finally, using cocultures of fluorescently labeled PDAC cells and a multiplexed sgRNA array targeting multiple tumor specific PAMs, we demonstrate selective cell killing of the targeted cell line. Importantly, deep sequencing of patient-matched normal lymphocytes lacking the tumor-specific PAMs treated with the same sgRNA array exhibited no editing at the targeted loci. This work establishes a bioinformatic platform for the discovery of tumor-specific CRISPR targets in the context of metastatic disease and demonstrates selective killing to cancer cells while sparing the patient’s normal cells. These data establish the proof of principle for a gene therapy approach targeting metastatic disease. Citation Format: Kirsten Bowland, Selina Shiqing K. Teh, Alyza Skaist, Ralph H. Hruban, Nicholas J. Roberts, Chrisine Iacobuzio-Donahue, James R. Eshleman. CRISPR-Cas9 targeting of somatic mutations selectively kills cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB357.
Abstract CT135: A pilot clinical study of orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors
Authors: Jeffrey Bacha, Dennis Brown, Sarath Kanekal, Neil Sankar, Lorena Lopez, Noymi Yam, Lars Wagner, James Geller, Markos Leggas, Patrick Thompson, Javier Osterheld
Journal: Cancer Research (2023)

Abstract Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also used off-label to treat a range of adult and pediatric tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days in combination with other agents such as temozolomide has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001). Protracted administration schedule of intravenous irinotecan is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. Methods: Eligibility: Up to 20 patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 110mg/m2/day will be studied in combination with fixed-dose temozolomide using a standard 3 + 3 phase I design. In the event the starting dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; comparative intrapatient pharmacokinetics of irinotecan and its metabolites will be assessed. This trial is ongoing (CT.gov: NCT04337177), with no DLT observed to date. Citation Format: Jeffrey Bacha, Dennis Brown, Sarath Kanekal, Neil Sankar, Lorena Lopez, Noymi Yam, Lars Wagner, James Geller, Markos Leggas, Patrick Thompson, Javier Osterheld. A pilot clinical study of orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT135.
Abstract LB194: A small molecular-weight anti-lag-3 peptide inhibits colon tumor growth
Authors: Mohammed Alahmari, Umar-Farouk Mamani, Yuhan Guo, Chien-Yu Lin, Mohammed Nurudeen Ibrahim, Yongren Li, Kun Cheng
Journal: Cancer Research (2023)

Abstract Lymphocyte activation gene-3 (LAG-3) has emerged as a promising target for cancer immunotherapy. It is expressed on activated CD4+ and CD8+ T cells, and on the surface of B cells, natural killer cells, and dendritic cells (DC). It has also been found to be highly expressed on activated T cells upon treatment with monoclonal antibodies targeting the PD-1/PD-L1 pathway, which may explain the resistance mechanism of monotherapy. Several anti-LAG-3 antibodies are being examined in clinical trials to treat different types of cancers. Despite their specificity and affinity, antibody-based checkpoint inhibitors are hampered by poor tumor permeability and high production costs. In this study, we aimed to discover a small peptide-based anti-LAG-3 inhibitor using a novel biopanning technique developed in our laboratory. We discovered several anti-LAG-3 inhibitor peptides, and the CMA16 peptide showed the highest stability and blocking efficacy. The peptides were synthesized by the solid-phase peptide synthesis using PurePepTM Chorus synthesizer (Gyros Protein Technologies, Tucson, AZ). The molecular weights and purity were confirmed by mass spectrometry and HPLC, respectively. To evaluate the function of the CMA16 peptide, a series of in vitro functional assays including binding ELISA, serum stability and cell viability assays were performed. In vivo anti-tumor activity of the peptides was examined in five-week-old C57BL/6 mice bearing MC38 cells. CMA16 significantly inhibited the growth of MC38 tumors. Quantification of CD8+ tumor-infiltrating cells revealed a significant increase in this type of immune cells in the group of mice treated with CMA16. These findings support the further development of the CMA16 peptide as potential anti-LAG-3 inhibitor for cancer immunotherapy. Citation Format: Mohammed Alahmari, Umar-Farouk Mamani, Yuhan Guo, Chien-Yu Lin, Mohammed Nurudeen Ibrahim, Yongren Li, Kun Cheng. A small molecular-weight anti-lag-3 peptide inhibits colon tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB194.